Editorial: Time to Genotype—Genetic Risk and Prognosis in Steatotic Liver Disease. Authors' Reply

Abstract

We thank Drs. Mancina and Romeo for their comments and for highlighting the importance of genetic markers as prognostic tools in steatotic liver disease (SLD) [1]. We agree with their statement that early genotyping, especially for high-impact variants such as PNPLA3 and TM6SF2, could meaningfully change disease trajectories in clinical practice by identifying individuals at risk for major adverse liver outcomes (MALO) [2]. As our meta-analysis demonstrated, genetic risk alleles are not only associated with disease onset but can stratify risk for cirrhosis, hepatocellular carcinoma, liver-related mortality and other key outcomes [3].

Most published studies to date have focused on hepatic outcomes, yet the field is rapidly evolving to explore broader implications of genetic variation in SLD. Genetics may help refine disease subgroups and explain heterogeneity in disease trajectory in which some patients die of liver disease while many more never develop cirrhosis but die instead of cardiovascular disease and cancer. As recent genome-wide association studies have illustrated, genetic risk variants in SLD not only influence disease severity but also define biologically distinct subgroups with different distributions of cardiometabolic comorbidities and risk of cardiovascular or hepatic outcomes [4-6]. For example, two recent studies studied ‘partitioned’ polygenic risk scores (PRS) based on subsets of SLD-promoting alleles [5, 6]. While the partitions were defined slightly differently in the two studies, across both studies one PRS group included alleles that impaired hepatic lipid export but reduced serum/plasma lipids (exemplified by alleles in PNPLA3 and TM6SF2) and were associated with markedly higher risk of MALO but lower risk of cardiovascular disease, and a second group promoted de novo lipogenesis (exemplified by GCKR and TRIB1 variants) and resulted in smaller increases in MALO but large increases in cardiovascular disease.

Genetics may eventually inform treatment selection. Recent studies have suggested that carriage of the PNPLA3-rs738409-G risk allele is associated with larger ALT reductions in response to semaglutide treatment [7] and greater reductions in liver fat content measured on magnetic resonance imaging following bariatric surgery [8]. In contrast, there was no association between PNPLA3, TM6SF2 or HSD17B13 genotype and histologic response to resmetirom [9]. In parallel, two first-in-human trials of PNPLA3-targeted gene therapies demonstrated that genetic variants may act not only as risk markers but also as treatment targets [10]. Additional real-world studies will be required to understand if genetics has a role in predicting response to non-targeted therapy and how gene therapy (if efficacious in phase 3 trials) fits in treatment algorithms alongside approved non-targeted treatments such as resmetirom or semaglutide.

We agree with Drs. Mancina and Romeo that the time has come to more systematically implement genotyping into SLD care pathways. As we noted in our systematic review, key next steps include expanding longitudinal data (e.g., incidence of hepatic or cardiovascular events, changes in time in non-invasive tests), assessing extrahepatic and treatment response outcomes, and evaluating the clinical utility, acceptability to patients, and cost-effectiveness of incorporating genotyping into routine care. These efforts will be critical to advancing the field of precision hepatology.

Matthew Kubina: conceptualization, investigation, writing – original draft, methodology, validation, visualization, writing – review and editing. Vincent L. Chen: conceptualization, investigation, writing – original draft, writing – review and editing, visualization, methodology, supervision, resources, validation.

V.L.C. received grant support from KOWA, Ipsen and AstraZeneca (to University of Michigan). M.K. declares no conflicts of interest.

This article is linked to Kubina et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70256 and https://doi.org/10.1111/apt.70269.